Background: The major histocompatibility complex (MHC) is the most important genomic region that contributes to the
risk of graft versus host disease (GVHD) after haematopoietic stem cell transplantation. Matching of MHC class I and II genes
is essential for the success of transplantation. However, the MHC contains additional genes that also contribute to the risk of
developing acute GVHD. It is difficult to identify these genes by genetic association studies alone due to linkage
disequilibrium in this region. Therefore, we aimed to identify MHC genes and other genes involved in the pathophysiology
of GVHD by mRNA expression profiling.
Methodology/Principal Findings: To reduce the complexity of the task, we used genetically well-defined rat inbred strains
and a rat skin explant assay, an in-vitro-model of the graft versus host reaction (GVHR), to analyze the expression of MHC,
natural killer complex (NKC), and other genes in cutaneous GVHR. We observed a statistically significant and strong up or
down regulation of 11 MHC, 6 NKC, and 168 genes encoded in other genomic regions, i.e. 4.9%, 14.0%, and 2.6% of the
tested genes respectively. The regulation of 7 selected MHC and 3 NKC genes was confirmed by quantitative real-time PCR
and in independent skin explant assays. In addition, similar regulations of most of the selected genes were observed in
GVHD-affected skin lesions of transplanted rats and in human skin explant assays.
Conclusions/Significance: We identified rat and human MHC and NKC genes that are regulated during GVHR in skin explant
assays and could therefore serve as biomarkers for GVHD. Several of the respective human genes, including HLA-DMB, C2,
AIF1, SPR1, UBD, and OLR1, are polymorphic. These candidates may therefore contribute to the genetic risk of GVHD in
patients.

Copyright 2011 Novota et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.